Benzopyran selective estrogen receptor modulators (SERMs): Pharmacological effects and structural correlation with raloxifene

Grese, Timothy A.; Sluka, James P.; Bryant, Henry U.; Cole, Harlan W.; Kim, John R.; Magee, David E.; Rowley, Ellen R.; Sato, Masahiko

doi:10.1016/0960-894x(96)00141-2

Cited by 21 publications

(29 citation statements)

References 17 publications

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“…Thus, the coplanar orientation of the side chain in tamoxifen and in compound 2 may contribute to the uterine stimulation that is observed with these compounds, whereas raloxifene and compound 3 produce little or no stimulation. Other compounds, in which the side chain is oriented orthogonally to a benzopyran ring system also have been reported to lack uterotrophic effects (14). The ability of raloxifene and compound 3 to function as tissueselective estrogen agonists is evidenced by their effects on bone mineral density and serum cholesterol.…”

Section: ϫ6mentioning

confidence: 99%

“…Molecular modeling studies have indicated that this simple structural modification produces a drastic change in the orientation of the basic side chain, from a coplanar orientation in 4-hydroxytamoxifen to a nearly orthogonal orientation in raloxifene (Figs. 6 and 7) (14). (The two rotomers of raloxifene in which the side chain occupies this orientation are enantiomeric in nature and equivalent in energy.)…”

Section: ϫ6mentioning

confidence: 99%

“…Indeed, it has been hypothesized that a series of liganddependent conformations exist and that each of these conformations may influence a unique subset of estrogen-responsive genes (9,10). A logical extension of this hypothesis is the dependence of ER conformation on the structural features and molecular conformation of individual ligands (11)(12)(13)(14). The recent characterization of a new ER isoform, ER␤, adds a further layer of complexity, because ligands with different structural characteristics may exhibit different binding profiles depending on which ER isoform is being evaluated (15,16).…”

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confidence: 99%

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Molecular determinants of tissue selectivity in estrogen receptor modulators

Grese

Sluka

Bryant

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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225

160

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Interaction of the estrogen receptor͞ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist͞antagonist effects. Both agents antagonize the effects of estrogen on mammary tissue while mimicking the actions of estrogen on bone. However, tamoxifen induces significant stimulation of uterine tissue whereas raloxifene does not. We postulate that structural differences between raloxifene and tamoxifen may influence the conformations of their respective receptor͞ligand complexes, thereby affecting which estrogen-responsive genes are modulated in various tissues. These structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B) different substituents on the basic amine, (C) incorporation of the stilbene moiety into a cyclic benzothiophene framework, and (D) the imposition of a carbonyl ''hinge'' between the basic amine-containing side chain and the olefin. A series of raloxifene analogs that separately exemplify each of these differences have been prepared and evaluated in a series of in vitro and in vivo assays. This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane. This three-dimensional array is dictated by a single carbon atom in the hinge region of raloxifene. These data indicate that differences in tissue selective actions among benzothiophene and triarylethylene estrogen receptor modulators can be ascribed to discrete ligand conformations.

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Section: ϫ6mentioning

confidence: 99%

Section: ϫ6mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular determinants of tissue selectivity in estrogen receptor modulators

Grese

Sluka

Bryant

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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225

160

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“…Thus substitution in the piperidine ring that decreases charge functionality at atom C 26 will increase inhibitory activity. These results are further adjudged with the SAR studies [44,45], where pharmacophoric groups of raloxifene are described as importance of benzothiophene core, 7-phenolic hydroxyl group, ketonic 'hinge' and the basic amine chain for binding activity. Again in the model (Eq.…”

Section: Qsar Studiesmentioning

confidence: 66%

Pharmacophore mapping of arylbenzothiophene derivatives for MCF cell inhibition using classical and 3D space modeling approaches

Mukherjee¹,

Nagar²,

Mullick³

et al. 2008

Journal of Molecular Graphics and Modelling

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“…Two of these agents are in widespread clinical use: clomiphene (Serophene") is used most commonly to initiate or augment ovulation by antagonizing estrogen's action at the hypothalamus and pituitary, thereby accentuating the release of gonadotro pins during the follicular phase [ 17]; as mentioned above, tamoxifen (Nolvadex®) is an effective agent for the treat ment of breast cancer, particularly ER-positive tumors in postmenopausal women [18]. Recently, toremifene (Fareston®) was also approved for treatment of advanced breast cancer [19] raloxifene (formerly keoxifcne), currently being evaluat ed for the prevention and treatment of osteoporosis [20], benzopyrans [21], tetrahydronaphthylencs such as CP 336,156, and structurally distinct molecules such as ormeloxifene (centchroman) [22] (fig. 1).…”

Section: Antiestrogensmentioning

confidence: 99%

In Search of Optimal Long-Term Female Hormone Replacement: The Potential of Selective Estrogen Receptor Modulators

Mitlak¹,

Cohen²

1997

Horm Res

125

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Selective estrogen receptor modulators (SERMs) comprise a group of structurally diverse compounds which are distinguished from estrogens by their ability to interact with the estrogen receptor but to act as either an estrogen agonist or antagonist depending on the target tissue and hormonal milieu. The mechanisms by which SERMs elicit tissue-specific responses are being intensively investigated, and recently a novel pathway for estrogen receptor-mediated gene activation by the SERM raloxifene has been demonstrated. The tissue-specific activity of SERMs suggests that they may be clinically useful as, for example, potential substitutes for long-term female hormone replacement therapy. Large-scale clinical testing currently in progress for raloxifene, and soon to begin for other SERMs, will evaluate this important potential.

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Benzopyran selective estrogen receptor modulators (SERMs): Pharmacological effects and structural correlation with raloxifene

Cited by 21 publications

References 17 publications

Molecular determinants of tissue selectivity in estrogen receptor modulators

Molecular determinants of tissue selectivity in estrogen receptor modulators

Pharmacophore mapping of arylbenzothiophene derivatives for MCF cell inhibition using classical and 3D space modeling approaches

In Search of Optimal Long-Term Female Hormone Replacement: The Potential of Selective Estrogen Receptor Modulators

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